5th lecture - hypnotics & sedatives Flashcards
define neuroleptic
(of a drug) tending to reduce nervous tension by depressing nerve functions; are both tranquillizers & antipschyotics.
function of the Cerebral cortex
consciousness, memory, thought (cortical functions)
function of the brain Centres in the subcortical regions
emotions, moods, experiences/perception (subcortical functions)
psychosedative effect =
Depression of cortical brain function
psychostimulation =
Stimulation of cortical brain function
euphoric, psychostimulatory drugs have what type of effects
Psychological stimulation
Neurosis means
a neurotic disorder, irritability or other such effects resulting from psychological overload.
involves symptoms of stress (depression, anxiety, obsessive behaviour, hypochondria) but not a radical loss of touch with reality.
In veterinary medicine neuroleptics and tranquilizers are described as one group of drugs, called:
major tranquilizers.
antipsychotics/anti-hallucinogenics are also known as
neuroleptics
overall depressant effect on the CNS
some subgroups of neuroleptics include: (4)
Phenothiazines (e.g. Plegicil/ace)
Thioxanthenes
Butyrophenones
Indoles (e.g. ondis and tadalafil)
Example of a common phenothiazine used in vet med
acepromazine (Plegicil)
example of a butyrophenone
(neuroleptic subgroup)
azaperone is used in vet med
example of an indole
(neuroleptic subgroup)
reserpine
neuroleptics pharmacokinetics (3)
Absorption is good,
they penetrate the blood-brain barrier, metabolism occurs in the liver.
neuroleptics mechniams of action
They suppress all mediatory systems in the brain and in the periphery:
adrenergic,
cholinergic,
histaminergic ,
serotonergic,
and dopaminoreactive systems.
The main effect and also secondary effects of neuroleptics are primarily related to the
dopamine blocking effect as the dopaminergic transmission in the central nervous system is blocked.
pathway from Tyrosine to Noradrenaline
Tyrosine, L-DOPA, Dopamine, Noradrenaline
Dopamine is a mediator with a catecholamine structure, mainly functioning in the brain structures related to
regulation of the psyche/ psychological domain: striatum, hypothalamus, hippocampus, mesolimbic structures and the fourth ventricle.
name dopamine receptors
5 subtypes are distinguished.
Pharmacologically important D1, D2 and D3.
The effect of neuroleptics is realised through D2 receptors.
Dopamine is broken down by
MAO and COMT.
monoamine oxidase
catechol O methyltransferase
neuroleptic antipshyotic effect is due to the blocking of what?
Antipsychotic effect due to dopamine blocking effect, limbic and cortical dopaminergic transmissions are blocked.
neuroleptic sedative effect is due to the blocking of what?
Sedative due to cholino and histamine blocking effect.
Cardiovascular effects of neuroleptics
Blockade of the central and peripheral effects of catecholamines:
Alfa-blockade = eripheral vasodilation
Arterial hypotension, even up to shocklike conditions especially in compromised patients.
define intrathecal
introduced into or occurring in the space under the arachnoid membrane of the brain or spinal cord.
Respiratory effects of neuroleptics
Clinical doses have little effect upon respiratory activity.
Respiratory rate is often depressed, but minute volume remains normal.
Respiratory depression may be exaggerated when phenothiazines are administered with other CNS respiratory depressants (opioids, isoflurane) or in high doses.
Musculosceletal effects of neuroleptics
Phenothiazines provide good muscle relaxation and are often used in conjunction with anesthetics that do not provide muscle relaxation or that result in muscle rigidity
(e.g. ketamine).
neuroleptics and Thermoregulation (2)
Phenothiazines alter thermoregulation by decreased catecholamine binding in the hypothalamus (where thermoregulation is controlled centrally),
as well as by altering vasomotor tone in the peripheral vessels that participate in heat retention and elimination.
neuroleptics’ effect on blood (2)
Acepromazine has been shown to decrease platelet aggregation – should be used with caution in patients with any coagulopathy or thrombocytopenia.
Phenothiazines markedly reduce the hematocrit of animals. They cause splenic sequestration of red blood cells and markedly reduce the hematocrit level.
neuroleptics’ Interactions with other medicinal products.
NL increase the potency of hypnotics without causing any sleepiness effect by themselves.
They potentiate the effect of general anaesthetics.
They increase the potency of analgesics without having any analgesic effect by themselves.
They potentiate the effect of muscle relaxants.
neuroleptics Should be used cautiously with any drugs that also produce
vasodilation or hypotension.
e.g. beta blockers
neuroleptic contraindications
Phenothiazines should not be used in patients that are dehydrated, hypovolemic, bleeding, or in shock (vasodilation).
Not in patients with coagulopathies or thrombocytopenia.
Use cautiously in boxer dogs, brachiocephalic dogs, breeding stallions and debilitated animals.
Butyrophenone (subgroup of neuroleptics) derivatives, in general, have a similar effect to
phenothiazines (another neuroleptic subgroup)
Azaperone is mainly used in swine to prevent
aggression when mixing groups of animals and during transport.
Tranquillizers are substances that
dampen negative emotions
(anxiety, fear, aggression),
in addition they have a sedative,
antiepileptic and muscle relaxant effect.
What are ataractic drugs?
an agent that has a calming or quieting effect, producing a state of ataraxy (= serene calmness).
Ataractic drugs can also be termed “muscle relaxant sedative tranquillizers”.
examples of Ataractic drugs or muscle relaxant sedative tranquillizers
Meprobamate &
Derivatives of benzodiazepine:
Diazepam
Midazolam
Lorazepam etc.
tranquilizer half-life
Half-life in animals is couple of hours, but accumulation is frequently experienced.
tranquilizer pharmacokinetics
Administered both through the oral and parenteral route.
absorbed well,
penetrates the blood-brain barrier and placental barrier.
Metabolised in the liver, resulting in the occurrence of enzyme induction.
tranquilizer mechanism of action
The effect is through
benzodiazepine receptors, gamma-aminobutyric acid (GABA) receptors (main effect) and also barbiturate receptors.
tranquillizers impact the chloride ionophore complex (movement of Cl ion into the cell).
what is the main receptor-type in the context of tranquilizer mechanism of action
gamma-aminobutyric acid (GABA) receptors (main effect)
No 1 drug against convulsions
diazepam
-> Relaxation of skeletal muscles.
Benzodiazepine cardiovascular effect
reduction in cerebral blood flow.
Cardiovascular effects of tranquiilizers
Clinical doses cause minimal cardiovascular depression.
With higher doses there are reductions in mean arterial blood pressure and systemic vascular resistance, and a reduction in myocardial oxygen consumption.
Musculosceletal effects of tranquilizers
Benzodiazepines potentiate the GABA-ergic-mediated muscle relaxation – anticonvulsant effect.
Adverse effects of tranquilizers
Transient period of agitation, vocalization, excitement, muscle fasciculations, ataxia (especially in dog, cat, horse).
It is recommended to use other agents in combination with benzodiazepines.
When used alone, they can cause unpredictable results.
Contraindications of tranquilizers
Patients with hypersensitivity to benzodiaszepines,
hepatic dysfunction.
Renal disease is a contraindication for basically all drugs.
Benzodiazepine antagonists
flumazenil
Flumazenil competitively antagonizes the actions of what types of drugs
benzodiazepines/GABA-agonists.
It does not antagonize the CNS effects of other sedative-hypnotics.
due to drug reactions, α2 adrenomimetics are used in combination with
sedatives or
neuroleptanalgesic drugs.
α2 adrenomimetics are pretty much only used as sedatives in veterinary medicine.
In human medicine, one substance belonging to the same group is used for hypertension. It is called what?
clonidine is used in the treatment of hypertension in people.
the oldest active alfa2 adrenomimetic substance
xylazine (Rompun)
analgesic, sedative, muscle relaxant.
alfa2 adrenomimetic Pharmacokinetics
administered through injection.
bioavailability is highly variable.
Metabolism is quick, many metabolites are created.
The half-life differs by species of animal, it also depends on the particular drug.
alfa2-adrenomimetics Pharmacodynamics
Has a centralised effect, stimulates α2 adrenergic receptors.
Inhibits the release of noradrenaline in adrenergic synapse.
There are also peripheral α-adrenomimetic effects.
CNS effects of alfa2 adrenomimetics
Reliable sedation by activation of α2 receptors in locus ceruleus nucleus located in the brainstem. Different species react differently.
However, activation of αONE receptors in the CNS will cause agitation, increased locomotor activity – an animal may show paradoxical excitement or movement.
analgesia of alfa2 adrenomimetics
Analgesic properties are similar to those of morphine (a narcotic analgesic), although unlike morphine, the substance does not cause central nervous system stimulation but rather sedation and depression.
alfa 2 adrenomimetic effect on the GI tract
GI motility and acid secretion is reduced.
Inhibition of the alfa2 impulses is accompanied by activation of the vomiting centre, therefore dogs and cats often experience vomiting as a side effect. Vomiting cannot be inhibited using α-adrenoblockers.
Cardiovascular effects of alfa2-adrenomimetics
A Biphasic response occurs, involving an initial and a secondary resposne.
TLDR: increase in parasympathetic tone, neg. inotrope; but peripherally, both α1 & α2 receptors activated. Increase in pressure, then baroreceptor-mediated reflex bradycardia.
Describe the Initial phase of the biphasic cardiovascular response of alfa2-adrenomimetics
activation of central α2 receptors reduces the sympathetic outflow (reduced NA), thereby increasing parasympathetic tone – there is a negative inotropic, chronotropic and dromotropic effect on the heart.
Peripherally, α1 and α2 receptors are activated in the blood vessels causing an increase in arterial blood pressure after which baroreceptor-mediated reflex bradycardia follows. Thus Patients are hypertensive and bradycardic.
describe the Second phase of the biphasic cardiovascular response of alfa2-adrenomimetics
heart rate remains low,
blood pressure decreases from the previous hypertensive, thus patients are hypotensive and bradycardic.
At therapeutic doses α2 agonists decrease cardiac output in most species by more than
50%
It is due to baroreceptor reflex and concomitant reduction in stroke volume, increased afterload, low catecholamines level, coronary vasoconstriction and reduced myocardial oxygen consumption.
Respiratory effects of alfa2-adrenomimetics
In general α2 agonists tend to cause a centrally mediated reduction in respiratory rate and minute ventilation.
Although, the respiratory depression is not as great compared with other anesthetics (e.g. opioids).
alfa2-adrenomimetic effects on Reproductive organs
In pregnant animals, low doses of α2 agonists can decrease myometrial contractions of uterus,
high doses increase contractions.
In the nongravid uterus myometrial contractions can be observed at any dose of α2 agonists.
Differences between species and drugs!
Some conflicting info in literature.
most sensitive species to alfa2-adrenomimetics
Ruminants are the most sensitive, cattle’s dosage is 1/10 of horses’ dosage.
in which species are alfa2-adrenomimetics ineffective
are ineffective in pigs, doses are very large so no point
most sensitive dog breeds to alfa2-adrenomimetics
Irish Setters and Basset Hounds are the most sensitive.
Do not administer alfa2-adrenomimetics in combination with
adrenaline as xylazine makes the heart extremely sensitive to the effect of adrenaline.
contraindications for alfa2-adrenomimetics
It is not recommended in case of:
tendency for arrhythmia hypotension, shock renal impairment liver impairment epilepsy (as xylazine predisposes to cramping)
Do not administer in the last month of gestation - abortion, premature birth.
2 examples of Antidepressants in vet med
Fluoxetine (preparation Reconcile/Prozac)
Clomipramine (preparation Clomicalm)
Indications for antidepressant use in vet med
for dogs in the event of separation anxiety-related disorders that result in irritation, unintentional defaecation and urination.
Fluoxetine is what type of drug
Selective serotonin reuptake inhibitor.
Does not have a sedative effect.
Fluoxetine Must not be administered together with
drugs that increase the risk of abnormal muscle contractions (e.g. Phenothiazines),
other serotonergic substances,
monoamine oxidase inhibitors,
tricyclic amines (Clomipramine).
Clomipramine is what type of drug
Non-selective serotonin reuptake inhibitor, tricyclic amine.
Clomipramine Inhibits the reuptake of
serotonin and noradrenaline in the neurons.
Clomipramine - a potent selective 5-HT (serotonin )reuptake inhibitor, its metabolite desmethylclomipramine is a potent selective noradrenaline reuptake inhibitor.
In addition, there is an anticholinergic effect through the antagonism of muscarinic receptors.
Mirtazapine indications
For body weight gain in cats experiencing poor appetite and weight loss resulting from chronic medical conditions.
mirtazapine is what type of drug
an α2-adrenergic receptor antagonist noradrenergic and serotonergic antidepressant drug.
The exact mechanism by which mirtazapine induces weight gain appears to be multifactorial.
The effect of neuroleptics is realised through what receptor type?
D2 receptors
Neuroleptic hypothermic effect is due to the blocking of what?
Hypothermic effect due to serotonin blocking effect, linked to the neuroleptic action on the thermo-regulatory centre located in the hypothalamus.
neuroleptic antiemetic effect is due to the blocking of what?
Antiemetic effects due to dopamine blocking effect.
The effect is strong in humans, dogs and monkeys while it is weak in cats.
